Pharmaceutical composition comprising neptinib or salt thereof and method for controlling impurity thereof

ABSTRACT

A pharmaceutical composition including neptinib is provided. The composition includes neptinib or a pharmaceutically acceptable salt thereof, and an excipient at a low risk of compatibleness. Furthermore, the pharmaceutical composition of the present invention may also include pharmaceutically acceptable organic acid or inorganic acid as a stabilizer. The content of impurity A maintains a non-significant increase in the long-term and accelerated stability investigation for the pharmaceutical composition.

FIELD OF THE INVENTION

The present invention relates to a kind of pharmaceutical composition.

BACKGROUND OF THE INVENTION

(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide having the structure as shown in the formula(II), is a newly developed “tinib” drug for EGFR-mutated non-small celllung cancer as well as EGFR-mutated and Her2-overexpressed non-smallcell lung cancer, and it is named neptinib. The remarkable feature ofneptinib and its acceptable salts such as dimaleate, xylenesulfonate andhydrochloride is that it is highly prone to produce a specific impurityA, whose possible structure has been identified as shown in the formula(I):

Taking the main ingredient itself as a control, the relative retentiontime of impurity A is about 0.50-0.52. More particular, through thestudy of neptinib and its salt forms and crystal forms, a salt-typeactive ingredient with a stable crystal form has been identified. Whenonly the active ingredient is present, its properties are relativelystable, and under the influence of various factors or after anaccelerated stability test at 40° C. for 6 months, there is nosignificant change in the content of impurities in the activeingredient. However, when the active ingredient is combined withexcipients, its stability tend to lowered, and impurity A emerges veryeasily which accounts for the largest amount of impurity in the activeingredient.

In order to prevent significant increase in the content of impurity A,through extensively compatibility studies of the active ingredientneptinib or its salt with excipients, the present inventors finally hasfound a group of compositions with low compatibility risks. Under thecondition of strictly controlled storage temperature, the content ofimpurity A produced in the composition can be controlled within theacceptable limits specified by the relevant technical guidelines. Sincethe lower storage temperature adds additional cost and requires specialmanagement measures for practical use, transportation and storage, inorder to achieve convenient storage and transportation of neptinibpreparations under relatively less strict conditions, the inventors ofthe present application further studied the production mechanisms ofimpurity A and found that based on the above compositions with a lowcompatibility risk, the addition of acids can inhibit the production ofimpurity A, thereby better controlling the content of impurity A in thecomposition.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a pharmaceuticalcomposition comprising neptinib. The pharmaceutical compositioncomprises neptinib or a pharmaceutically acceptable salt thereof, andone or more excipients selected from the group consisting of lactose,mannitol, starch-lactose compound, microcrystalline cellulose-lactosecompound, crospovidone, colloidal silica and glyceryl behenate.

In the pharmaceutical composition of the present invention, neptinib isan active free base, and its acceptable salt refers to various saltsformed by the free base and acid radicals. Such acid radicals include,but are not limited to, hydrochloric acid, toluenesulfonic acid,dimaleic acid, acetic acid, succinic acid, sulfonic acid,methanesulfonic acid and trifluoromethanesulfonic acid. In the presentinvention, preferred salt is xylenesulfonate, especially a hydrate ofxylenesulfonate, and the most preferred is a xylenesulfonate containing1.0-1.5 crystal water in its molecule.

In the pharmaceutical composition of the present invention, the amountof neptinib or a pharmaceutically acceptable salt thereof is preferably0.05%-12% (by weight), and more preferably 0.1%-7% (by weight).

In a preferred embodiment, the pharmaceutical composition comprisingneptinib of the present invention comprises the following components byweight:

Neptinib or a pharmaceutically acceptable salt thereof 0.1%-7%

Lactose and mannitol combination 70-96%

Crospovidone 1-10%

Colloidal silica 0.5-3%

Glyceryl behenate 0.5-3%.

Further, the composition may also comprise a pharmaceutically acceptableorganic or inorganic acid as a stabilizer. The content of impurity Amaintains at low level and does not increase significantly in thelong-term and accelerated stability tests for the pharmaceuticalcomposition, and the impurity A has the structure as shown in theformula (I):

In a preferred embodiment, the pharmaceutical composition comprisingneptinib of the present invention comprises the following components byweight:

Neptinib or a pharmaceutically acceptable salt thereof 0.1%-7%

Filler 55%-90%

Disintegrant 1%-10%

Glidant 0.5%-3%

Lubricant 0.5%-3%

Stabilizer 0.1%-15%;

wherein the filler is one or more selected from the group consisting oflactose, mannitol, starch-lactose compound, and microcrystallinecellulose-lactose compound; the disintegrant is crospovidone XL orXL-10; the lubricant is glyceryl behenate; the glidant is colloidalsilica; and the stabilizer is selected from the group consisting ofbenzoic acid, citric acid, tartaric acid, malic acid, edetic acid, andlactic acid.

The stabilizing agent in the pharmaceutical composition of the presentinvention is preferably selected from the group consisting of citricacid, tartaric acid and malic acid.

In order to obtain a pharmaceutical composition of neptinib with stableproperties and limited degradation, the inventors of the presentapplication conducted extensive compatibility studies of the activeingredient of the pharmaceutical composition with various excipients.The inventors of the present application found that impurity A isgenerated significantly which has to be slickly controlled. According tothe compatibility studies, the inventors identified a group ofexcipients which can be used for formulation development with lowdegradtion risks, including lactose, mannitol, starch-lactose compound,microcrystalline cellulose-lactose compound, crospovidone, colloidalsilica, and glyceryl behenate.

It is satisfactory that the content of impurity A and other impuritiesin the obtained composition is identical to that in the activeingredient at day 0. The obtained composition and its dosage formsaccording to the present invention can still meet the limit requirementafter an accelerated stability test at a lower temperature (30±12° C.,RH 65±15%) for 6 months, indicating that the dosage forms can be storedfor a long period of time at a temperature below 25° C.

Since the lower storage temperature adds additional costs and requiresspecial management measures for practical use, transportation andstorage, the inventors have conducted further studies on the degradationmechanism of impurity A, which is shown in the following reaction scheme(1):

If the microenvironment of the active ingredient neptinib or its saltsis alkaline, the impurity A is easily generated, and the reaction iscontinuous and will not be suppressed by the accumulation of thedegradation product. Further, the inventors have found that the additionof certain inorganic or organic acids to the above-mentioned compositioncomprising the active ingredient neptinib or its salts and theexcipients selected in the present invention can suppress the generationof impurity A, and thus the acid can be used as a stabilizer. Therefore,a pharmaceutically acceptable organic or inorganic acid as a stabilizeris added to the composition, wherein the organic or inorganic acid isselected from the group consisting of benzoic acid, citric acid,tartaric acid, malic acid, edetic acid and lactic acid. Suchpharmaceutical composition can control the generation of impurities andthe long-term stability of the pharmaceutical composition is improved.

The compositions provided by the present invention are suitablyformulated into solid preparations including tablet, capsule, granuleand powder, wherein the tablet, in particular, contain a HPMC filmcoating.

The stability of the active ingredient limits the preparation process.For example, the active ingredient neptinib or its salts are sensitiveto moisture and heat, so processes such as wet granulation and dryingshould be avoided in the preparation process. In the embodiments of thepresent invention, preparation methods such as direct compressing ordirect filling are preferred. In addition, the possible changes in thecrystal form of the active ingredient should also be considered. Thepreparation method of the tablet is determined by the properties of theactive ingredient, and a preparation process that can maintain thestability of the active ingredient is preferred. In the practice of thepresent invention, dry granulation and then compression process ordirect powder compression process is preferred, and direct powdercompression is the most preferred. The preparation process includessieving, mixing, and compressing process, and does not involve heat andmoisture treatments, ensuring the maximum stability of the activeingredient. The tablet may be film-coated if needed, and the formulationof the film coating is preferably as simple as possible, wherein thefilm material in the coating formulation is preferably HPMC. Theplasticizer in the coating formulation is preferably an ester, such astriacetin, triethyl citrate. The color ingot in the coating formulationis preferably titanium dioxide. The ideas of the preparation method ofthe capsules are also consistent with that of the tablets, that is themoisture and heat is avoided, direct powder filling is preferred andsuitable excipients having good fluidity should be selected. Dependingon the weight of the contents to be filled, gelatin capsules sizes 1# to4# or HPMC capsules may be chosen. The granules can be obtained byconventional granulation techniques, such as wet granulation, drygranulation or fluid bed granulation followed by packing into suitablepackage bags. The powder is obtained by mixing the active ingredient andthe excipients and then directly packing it into suitable package bagsunder the premise of uniform mixing.

EXAMPLES

The following examples are intended to facilitate the person skilled inthe art to fully understand the technical solution and the intent of theinvention, in stead of limiting the scope of the invention. The activeingredient (API, neptinib xylenesulfonate) used in Examples 1-3 wassynthesized in pilot-scale by the inventors according to the methodsdescribed in Chinese Patent No. ZL201410822395.3 and ZL 201410826075.5,with the content of 99.8%-100.3% and moisture of 3.0-3.1% (determined byKarl Fischer method). Other related excipients are commerciallyavailable products.

Example 1: Selection of Excipients

TABLE 1 Results of API and excipients compatibility study Day 10Illumination Day 0 RH75% ± 5% RH92.5% ± 5% 60° C. ± 2° C. (4500 ± 5001x)Maximum Maximum Maximum Maximum Maximum API/ single Total single Totalsingle Total single Total single Total excipient impurity impurityimpurity impurity impurity impurity impurity impurity impurity impurityName ratio (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) API / 0.02 0.02 0.020.02 0.02 0.02 0.02 0.04 0.12 0.14 RRT1.21 RRT1.21 RRT1.22 RRT1.21RRT0.93 Lactose 1:10 0.02 0.02 0.02 0.02 0.02 0.06 0.04 0.06 0.16 0.26RRT1.22 RRT1.21 RRT1.21 RRT0.51 RRT0.93 Microcrystalline 1:10 0.02 0.020.05 0.08 0.04 0.08 1.19 1.21 0.13 0.20 cellulose RRT1.22 RRT0.93RRT0.51 RRT0.51 RRT0.93 Microcrystalline 1:10 0.02 0.02 0.05 0.07 0.040.07 0.20 0.22 0.14 0.17 cellulose-lactose RRT1.22 RRT0.93 RRT0.93RRT0.51 RRT0.93 compound Mannitol 1:10 0.02 0.02 0.02 0.02 0.01 0.040.04 0.04 0.14 0.23 RRT1.22 RRT0.93 RRT0.52 RRT0.51 RRT0.93Pregelatinized 1:10 0.02 0.02 0.10 0.14 0.14 0.19 0.86 0.88 0.11 0.14starch RRT1.22 RRT0.51 RRT0.51 RRT0.51 RRT0.93 Starch 1:10 0.02 0.020.18 0.22 0.14 0.16 2.53 2.55 0.12 0.22 RRT1.22 RRT0.51 RRT0.51 RRT0.51RRT0.93 Starch-lactose 1:10 0.02 0.02 0.02 0.03 0.03 0.05 0.02 0.05 0.140.19 compound RRT1.21 RRT1.21 RRT0.52 RRT0.52 RRT0.94 Crospovidone 1:100.02 0.03 0.08 0.14 0.06 0.12 0.11 0.15 0.15 0.26 RRT1.22 RRT0.33RRT0.32 RRT0.51 RRT0.93 Sodium 1:10 0.02 0.02 0.48 0.59 0.67 0.74 0.350.37 0.15 0.33 carboxymethyl RRT1.22 RRT0.51 RRT0.51 RRT0.51 RRT0.93starch Cross-linked 1:10 0.02 0.02 0.10 0.19 0.05 0.14 0.12 0.14 0.160.32 CMCNa RRT1.22 RRT0.51 RRT 0.81 RRT0.51 RRT0.93 L-HPC 1:10 0.02 0.020.13 0.20 0.11 0.14 2.45 2.76 0.14 0.29 RRT1.22 RRT0.51 RRT0.51 RRT0.52RRT0.93 Tartaric acid 1:10 0.02 0.02 0.02 0.02 0.02 0.05 0.04 0.06 0.120.21 RRT1.22 RRT0.93 RRT1.21 RRT0.51 RRT0.93 Citric acid 1:10 0.02 0.020.02 0.02 0.02 0.04 0.08 0.10 0.14 0.24 RRT1.22 RRT1.21 RRT1.21 RRT0.51RRT0.93 Malic acid 1:10 0.02 0.02 0.04 0.04 0.05 0.06 0.12 0.14 0.110.20 RRT1.22 RRT1.21 RRT1.21 RRT0.51 RRT0.93 Magnesium 1:10 0.07 0.220.04 0.08 0.14 0.23 0.48 0.53 0.11 0.32 stearate RRT0.66 RRT0.81 RRT0.51RRT0.51 RRT0.93 Sodium stearyl 1:10 0.06 0.13 0.08 0.14 0.55 0.65 18.3518.69 0.10 0.34 fumarate RRT0.51 RRT0.51 RRT0.51 RRT0.52 RRT0.93Glyceryl 1:10 0.02 0.02 0.02 0.02 0.02 0.04 0.02 0.02 0.34 0.45 behenateRRT1.22 RRT0.93 RRT0.51 RRT0.51 RRT1.39 Povidone 1:10 0.04 0.07 0.050.15 0.08 0.35 0.78 0.99 0.13 0.40 RRT0.51 RRT2.53 RRT0.32 RRT0.51RRT0.93 Colloidal 1:5  0.01 0.01 0.04 0.06 0.02 0.03 0.10 0.10 0.17 0.22silica RRT0.93 RRT0.29 RRT0.93 RRT0.51 RRT0.93 Empty gelatin 1:10 0.020.02 0.02 0.03 0.02 0.03 0.38 0.40 0.04 0.06 capsule RRT1.21 RRT1.21RRT1.21 RRT0.52 RRT0.94 HPMC 1:10 0.02 0.02 0.02 0.02 0.02 0.04 0.030.07 0.07 0.09 capsule RBT1.21 RRT1.21 RRT1.21 RRT0.20 RRT0.94 API-PVA1:10 0.03 0.08 0.50 0.61 0.63 0.74 6.04 6.21 0.12 0.30 RRT0.51 RRT0.51RRT0.51 RRT0.93 API -HPMC 1:10 0.03 0.07 0.06 0.12 0.08 0.13 0.91 0.960.10 0.14 RRT0.51 RRT0.51 RRT0.51 RRT0.94 API- 1:10 0.12 0.19 0.10 0.180.12 0.20 0.10 0.18 0.11 0.23 Triacetin RRT0.22 RRT0.22 RRT0.22 RRT0.22Drug-TiO₂ 1:10 0.03 0.09 0.04 0.09 0.06 0.12 0.96 1.80 0.47 1.25 RRT0.51RRT0.51 RRT0.51 RRT0.32 Core tablet - 24.4 0.03 0.09 0.19 0.29 0.32 0.481.39 1.45 0.20 0.36 PVA  g:15 g RRT0.51 RRT0.51 RRT0.51 RRT0.94 Coretablet - 24.4 0.03 0.07 0.07 0.13 0.12 0.31 0.82 0.87 0.15 0.15 HPMC g:15 g RRT0.51 RRT0.51 RRT0.51 RRT0.94 Core tablet - 24.4 0.13 0.200.13 0.18 0.13 0.18 0.13 0.22 0.30 0.63 Triacetin  g:15 g RRT0.22RRT0.22 RRT0.22 RRT1.46 Core tablet - 24.4 0.03 0.06 0.04 0.06 0.04 0.090.71 0.87 0.13 0.32 TiO₂  g:15 g RRT0.51 RRT0.51 RRT0.51 RRT0.94

Table 1 shows the results of the impurity content changes in the mixedpowder of the active ingredient and the excipients after 10 days ofstress testing, and the corresponding risk levels are classifiedaccording to the following criteria:

Level 1 (low risk): maximum single impurity is less than 0.1% and totalimpurity is less than 0.2%;

Level 2 (medium risk): maximum single impurity is 0.1-0.2% or totalimpurity is 0.2%-0.4%;

Level 3 (high risk): maximum single impurity is more than 0.2% or totalimpurity is more than 0.4%.

TABLE 2 Risk assessment of the API and excipients compatibilityAPI/excipient Risk level assessment value Excipient Type Excipient Nameratio RH75% RH92.5% 60° C. Illumination Total Filler Lactose 1:10 1 1 12 5 Microcrystalline 1:10 1 1 3 2 7 cellulose Microcrystalline 1:10 1 12 2 6 cellulose-lactose compound Mannitol 1:10 1 1 1 2 5 Pregelatinizedstarch 1:10 2 2 3 2 9 Starch 1:10 2 2 3 2 9 Starch-lactose 1:10 1 1 1 25 compound Stabilizer Tartaric acid 1:10 1 1 1 2 5 Citric acid 1:10 1 11 2 5 Malic acid 1:10 1 1 2 2 6 Disintegrant Crospovidone 1:10 1 1 2 2 6Sodium 1:10 3 3 3 2 11 carboxymethyl starch Cross-linked sodium 1:10 2 12 2 7 carboxymethyl cellulose L-HPC 1:10 2 2 3 2 9 Lubricant Magnesiumstearate 1:10 1 2 3 2 8 Sodium stearyl 1:10 1 3 3 2 9 fumarate Glycerylbehenate 1:10 1 1 1 3 6 Adhesive Povidone K29/32 1:10 1 1 3 2 7 GlidantColloidal silica 1:5  1 1 1 2 5 Empty Empty gelatin Packing 1 1 3 1 6capsule capsule Empty HPMC Packing 1 1 1 1 4 capsule Coating PVA 1:10 33 3 2 11 powder HPMC 1:10 1 1 3 2 7 ingredient Triacetin 1:10 2 2 2 2 8TiO₂ 1:10 1 1 3 3 8 API Neptinib 1 1 1 2 5 xylenesulfonate

From the risk assessment results in Table 2 it is clear that thecompositions comprising one or more ingredients of starch,pregelatinized starch, microcrystalline cellulose, sodium carboxymethylstarch, L-HPC, magnesium stearate, sodium stearyl fumarate and PVApresent a higher risk. While the compositions with one or severalingredients selected from lactose, mannitol, microcrystallinecellulose-lactose compound, starch-lactose compound, tartaric acid,citric acid, crospovidone, colloidal silica, and glyceryl behenate wereidentified low risks of compatibility.

Example 2: Preparation of Dosage Forms

The following examples show a method of preparing the dosage formscomprising neptinib xylenesulfonate as the active ingredient.

2.1 Preparation of Capsules and Powder Dosage Form of NeptinibXylenesulfonate

TABLE 3 The contents and compositions for preparation of capsules andpowder dosage form of neptinib xylenesulfonate SpecificationSpecification Specification Specification Component 1 2 3 4 Neptinib1.78 mg 5.33 mg 8.88 mg 17.76 mg xylenesulfonate (1 mg (3 mg (5 mg (10mg (calculated on neptinib) neptinib) neptinib) neptinib) the anhydrousbasis) Mannitol 120.78 mg  138.12 mg  236.12 mg  276.24 mg  Colloidalsilica 1.25 mg  1.5 mg  2.5 mg 3.0 Glyceryl 1.25 mg  1.5 mg  2.5 mg  3.0mg behenate Total weight  125 mg  150 mg  250 mg   300 mg

Preparation method: according to the contents and compositions shown inTable 3, the active ingredient neptinib xylenesulfonate was first passedthrough a 60-100 mesh sieve, and then mixed with mannitol, colloidalsilica, glyceryl behenate and passed through a 40-60 mesh sievetogether, yielding the final blending material. The finial blendingmaterial was directly placed in an automatic capsule filling machine,and filled to empty gelatin capsules of sizes 4#, 3# or 2# based on theweight of the contents.

2.2 Preparation of Granule Dosage Form of Neptinib Xylenesulfonate

TABLE 4 The contents and compositions for preparation of granule dosageform of neptinib xylenesulfonate Component Specification 1 Specification2 Specification 3 Specification 4 Neptinib xylenesulfonate 1.78 mg 5.338 88 mg 17.76 mg (calculated on the (1 mg (3 mg (5 mg (10 mg anhydrousbasis) neptinib) neptinib) neptinib) neptinib) Lactose monohydrate120.78 mg 138.12 mg 236.12 mg 276.24 mg Colloidal silica 1.25 mg 1.5 mg2.5 mg 3.0 Glyceryl behenate 1.25 mg 1.5 mg 2.5 mg 3.0 mg Total weight125 mg 150 mg 250 mg 300 mg

Preparation method: According to the contents and compositions shown inTable 4, the active ingredient neptinib xylenesulfonate was first passedthrough a 60-100 mesh sieve, and then was mixed with lactose monohydratein a high-speed shear granulator. Purified water was added forgranulation, and then was dried at 50-60° C. The dried granules werefinally blended with colloidal silica and glyceryl behenate and filledinto composite film bags.

2.3 Preparation of Tablets of Neptinib Xylenesulfonate

2.3.1

TABLE 5 The contents and compositions for preparation of tablets ofneptinib xylenesulfonate Component Specification 1 Specification 2Specification 3 Specification 4 Neptinib xylenesulfonate 1.78 mg  5.33mg 8.88 mg  17.76 mg  (calculated on the (1 mg (3 mg (5 mg (10 mganhydrous basis) neptinib) neptinib) neptinib) neptinib) Lactosemonohydrate 31.1 mg  37.8 mg 44.5 mg  89.0 mg  Mannitol 62.12 mg  75.62mg  89.12 mg  178.24 mg   Crospovidone 3.0 mg 3.75 mg 4.5 mg   9 mgColloidal silica 1.0 mg 1.25 mg 1.5 mg   3 mg Glyceryl behenate 1.0 mg1.25 mg 1.5 mg   3 mg Opadry coating powder   4 mg   5 mg   6 mg  12 mgTotal weight  104 mg  130 mg 156.0 mg  312.0

Preparation method: according to the contents and compositions shown inTable 5, the active ingredient neptinib xylenesulfonate was first passedthrough a 60-100 mesh sieve, the other excipients were passed through a40-60 mesh sieve. Then they were subjected to final blending andcompressing, and compressed into core tablets with diameter of 6 mm, 6mm, 7 mm and 9 mm respectively, according to the specifications 1-4. Thecoating material (HPMC, triacetin or titanium dioxide) was sprayed onthe core tablets. The surface temperature of the tablets was controlledin the range of 40-55° C. during film coating.

2.3.2

TABLE 6 The contents and compositions for preparation of tablets ofneptinib xylenesulfonate Component Specification 1 Neptinibxylenesulfonate (calculated 8.88 mg on the anhydrous basis) (5 mgneptinib) Lactose monohydrate 44.5 mg Microcrystalline cellulose 89.12mg  Crospovidone  4.5 mg Colloidal silica  1.5 mg Magnesium stearate 1.5 mg Opadry coating powder   6 mg Total weight 156.0 mg 

Preparation method: same as in Example 2.3.1.

2.3.3

TABLE 7 The contents and compositions for preparation of tablets ofneptinib xylenesulfonate Component Specification 1 Neptinibxylertesulfonate (calculated 8.88 mg  on the anhydrous basis) (5 mgNeptinib) Lactose monohydrate 44.5 mg  Pregelatinized starch 89.12 mg Crospovidone 4.5 mg Colloidal silica 1.5 mg Magnesium stearate 1.5 mgOpadry coating powder   6 mg Total weight 156.0 mg 

Preparation method: same as in Example 2.3.1.

2.3.4

TABLE 8 The contents and compositions for preparation of tablets ofneptinib xylenesulfonate Component Specification 1 Neptinibxylenesulfonate (calculated 8.88 mg  on the anhydrous basis) (5 mgNeptinib) Lactose monohydrate 44.5 mg  Microcrystalline cellulose 89.12mg  Sodium carboxymethyl cellulose 4.5 mg Colloidal silica 1.5 mgMagnesium stearate 1.5 mg Opadry coating powder   6 mg Total weight156.0 mg 

Preparation method: same as in Example 2.3.1.

2.3.5 Preparation of Neptinib Xylenesulfonate Tablets Containing aStabilizer

TABLE 9 The contents and compositions for preparation of tablets ofneptinib xylenesulfonate Component Specification 1 Specification 2Specification 3 Specification 4 Neptinib xylenesulfonate 1.78 mg  5.33mg  8.88 mg  17.76 mg  (calculated on the (1 mg (3 mg (5 mg (10 mganhydrous basis) Neptinib) Neptinib) Neptinib) Neptinib) Lactosemonohydrate 22.1 mg  26.6 mg  39.5 mg  79.1 mg Mannitol 44.12 mg  53.07mg  79.12 mg  158.14 mg  Crospovidone 2.4 mg 3.0 mg 4.5 mg   9 mgColloidal silica 0.8 mg 1.0 mg 1.5 mg   3 mg Glyceryl behenate 0.8 mg1.0 mg 1.5 mg   3 mg Tartaric acid   8 10 15 30  Opadry coating powder3.2 mg   4 mg   6 mg   12 mg Total weight 83.2 mg   104 mg  156.0 mg 312.0

Preparation method: The active ingredient neptinib xylenesulfonate wasfirst passed through a 60-100 mesh sieve. Tartaric acid was crushed andthen passed through an 80-120 mesh sieve. The sieved neptinib, tartaricacid and colloidal dioxide were pre-mixed, then subjected to finalblending together with other excipients and compressing. The blendingmaterial was compressed into core tablets with diameter of 6 mm, 6 mm, 7mm and 9 mm respectively, according to the specifications 1-4. Thecoating material (HPMC, triacetin or titanium dioxide) was sprayed onthe core tablets. The surface temperature of the tablets was controlledin the range of 40-55° C. during film coating.

2.3.6 Preparation of Neptinib Xylenesulfonate Tablets Containing aStabilizer

TABLE 10 The contents and compositions for preparation of tablets ofneptinib xylenesulfonate Component Specification 1 Specification 2Specification 3 Specification 4 Neptinib xylenesulfonate 1.78 mg  5.33mg  8.88 mg  17.76 mg  (calculated on the anhydrous (1 mg Neptinib) (3mg Neptinib) (5 mg Neptinib) (10 mg basis) Neptinib) Lactose monohydrate22.1 mg  26.6 mg  39.5 mg  79.1 mg Mannitol 44.12 mg  53.07 mg  79.12mg  158.14 mg  Crospovidone 2.4 mg 3.0 ma 4.5 mg   9 mg Colloidal silica0.8 mg 1.0 mg 1.5 mg   3 mg Glyceryl behenate 0.8 mg 1.0 mg 1.5 mg   3mg Malic acid 8 10 15 30  Opadry coating powder 3.2 mg   4 mg   6 mg  12 mg Total weight 83.2 mg   104 mg  156.0 mg  312.0

Preparation method: same as in Example 2.3.5.

Example 3: Detection of the Content of Impurity A

Accelerated stability test was carried out on the 5 mg coated tabletsprepared in Example 2.2 and Example 2.3. The method for detectingimpurity A and total impurity was shown as follows:

Equipment: Agilent 1260 series;

Column: XBridge Shield RP18 column (100×4.6 mm, 3.5 μm);

Mobile phase A: 0.05 mol/L potassium dihydrogen phosphate solution(adjusted to pH 7.2 with sodium hydroxide solution)-acetonitrile(20:80);

Mobile phase B: 0.05 mol/L potassium dihydrogen phosphate solution(adjusted to pH 7.2 with sodium hydroxide solution)-acetonitrile(40:60);

Linear gradient:

Time (mm) Mobile phase A Mobile phase B 0 74 26 8 54 46 20 54 46 30 0100 40 0 100 40.1 26 74 45 26 74

Detection wavelength: 247 nm;

Flow rate: 1.0 ml/min;

Column temperature: 30° C.;

Injection volume: 10 μl;

Solvent: acetonitrile-water (50:50).

TABLE 11 Accelerated stability test results of Examples 2.3.1-2.3.4 Testtime 0 month 1 month 1.5 months Total Total Total Impurity impurityImpurity impurity Impurity impurity Test condition A % % A % % A % %Example 2.3.1 ND 0.06 0.13 0.20 0.23 0.32 (specification 5 mg) 40 ± 2°C., RH75 ± 5% Example 2.3.2 ND 0.06 0.35 0.86 0.54 1.41 40 ± 2° C., RH75± 5% Example 2.3.3 ND 0.07 0.42 1.07 0.66 1.84 40 ± 2° C., RH75 ± 5%Example 2.3.4 ND 0.06 0.81 1.76 1.33 2.12 40 ± 2° C., RH75 ± 5%

From the above accelerated stability test results, it was found thatwithin 0-1.5 months, the contents of impurity A and total impurity inthe drug product of Examples 2.3.2, 2.3.3 and 2.3.4 was much higher thanthat of Example 2.3.1, and the impurity growth was significant.Therefore, the low-risk composition presented in the invention caneffectively reduce the generation rate of impurity A.

TABLE 12 Accelerated stability test results of Example 2.3.1, Example2.3.5 and Example 2.3.6 Test time 0 month 1 month 2 months 3 months 6months Total Total Total Total Total Impurity impurity Impurity impurityImpurity impurity Impurity impurity Impurity impurity Test condition A %% A % % A % % A % % A % % Example 2.3.1 0.03 0.07 0.13 0.21 0.22 0.320.33 0.43 0.40 0.49 (specification 5 mg) 30 ± 2° C., RH65 ± 5% Example2.3.1 0.03 0.07 0.16 0.23 0.34 0.43 0.49 0.58 0.94 1.08 (specification 5mg) 40 ± 2° C., RH75 ± 5% Example 2.3.5 0.02 0.07 0.02 0.06 0.02 0.070.03 0.08 0.04 0.12 (specification 5 mg) 30 ± 2° C., RH65 ± 5% Example2.3.5 0.02 0.07 0.03 0.11 0.03 0.1 0.04 0.15 0.05 0.17 (specification 5mg) 40 ± 2° C., RH75 ± 5% Example 2.3.6 0.02 0.03 0.04 0.07 0.06 0.090.09 0.14 0.16 0.20 (specification 5 mg) 30 ± 2° C., RH65 ± 5% Example2.3.6 0.02 0.03 0.05 0.08 0.07 0.12 0.10 0.14 0.17 0.22 (specification 5mg) 40 ± 2° C., RH75 ± 5%

As shown in the above accelerated test stability results, although thepharmaceutical excipients with relative low risks of compatibility wasused in the drug product of Example 23.1, the content of the specificimpurity A in the drug product still increased significantly when it wastested for six months under conditions of longer period of time andhigher temperature of the accelerated tests. Based on the composition ofExample 2.3.1, the acid according to the present invention was added toobtain the compositions of Examples 2.3.5 and 2.3.6. As demonstrated bythe results of the accelerated tests in Example 2.3.5 and Example 2.3.6,these specific compositions presented in this invention can overcome theissue of the impurity A controlling, ensuring that the content ofimpurity A does not increase significantly.

1. A pharmaceutical composition comprising neptinib, comprising:neptinib or a pharmaceutically acceptable salt thereof, and one or moreexcipients selected from the group consisting of lactose, mannitol,starch-lactose compound, microcrystalline cellulose-lactose compound,crospovidone, colloidal silica and glyceryl behenate.
 2. Thepharmaceutical composition according to claim 1, characterized in thatthe pharmaceutically acceptable salt of neptinib comprises neptinibdihydrochloride, neptinib dimaleate or neptinib xylenesulfonate.
 3. Thepharmaceutical composition according to claim 2, characterized in thatneptinib xylenesulfonate is a hydrate of neptinib xylenesulfonate. 4.The pharmaceutical composition according to claim 3, characterized inthat the hydrate of neptinib xylenesulfonate comprises 1.0-1.5 crystalwater in the neptinib xylenesulfonate molecule.
 5. The pharmaceuticalcomposition according to claim 1, characterized in that the compositioncomprises 0.05%-12% by weight of neptinib or a pharmaceuticallyacceptable salt thereof.
 6. The pharmaceutical composition according toclaim 5, characterized in that the composition contains 0.1%-7% byweight of neptinib or a pharmaceutically acceptable salt thereof.
 7. Thecomposition according to claim 6, characterized in that the compositioncomprises the following components by weight: Neptinib or apharmaceutically acceptable salt thereof 0.1%-7% Lactose and mannitolcombination 70-96% Crospovidone 1-10% Colloidal silica 0.5-3% Glycerylbehenate 0.5-3%.
 8. The pharmaceutical composition according to claim 1,characterized in that the composition further comprises apharmaceutically acceptable organic or inorganic acid as a stabilizer,wherein the content of impurity A does not increase significantly in thelong-term and accelerated stability test for the pharmaceuticalcomposition, and the impurity A has the structure as shown in theformula (I):


9. The pharmaceutical composition according to claim 8, characterized inthat the stabilizer is selected from the group consisting of citricacid, tartaric acid and malic acid.
 10. The pharmaceutical compositionaccording to claim 8, characterized in that the composition comprisesthe following components by weight: Neptinib or a pharmaceuticallyacceptable salt thereof 0.1%-7% Filler 55%-90% Disintegrant 1%-10%Glidant 0.5%-3% Lubricant 0.5%-3% Stabilizer 0.1%-15%, wherein thefiller is one or more selected from the group consisting of lactose,mannitol, starch-lactose compound, and microcrystallinecellulose-lactose compound, and the disintegrant is crospovidone XL orXL-10, and the lubricant is glyceryl behenate, and the glidant iscolloidal silica, and the stabilizer is selected from the groupconsisting of benzoic acid, citric acid, tartaric acid, malic acid,edetic acid, and lactic acid.
 11. A preparation comprising thepharmaceutical composition of claim 1, wherein its dosage form isselected from the group consisting of tablet, capsule, granule, andpowder.
 12. A preparation comprising the pharmaceutical composition ofclaim 1, wherein its dosage form is tablet coated with HPMC film.